2-alkoxy-5,6,7,8-tetrahydroquinoxaline derivatives, and production method and use thereof

ABSTRACT

Disclosed are a compound represented by formula (1) and a non-toxic salt thereof, a production method thereof, and a pharmaceutical composition for treating a serotonergic neuron-related disease comprising the same as an active ingredient: ##STR1## wherein R 1  represents a hydrogen atom or a lower alkyl group; R 2  represents a pyridyl group which is unsubstituted or substituted with 1 to 3 substituents each independently selected from the group consisting of a halogen atom, a lower alkyl group, a trifluoromethyl group, a lower alkoxy group, a carbamoyl group and a cyano group, or a pyrimidinyl group which is unsubstituted or substituted with 1 to 2 substituents each independently selected from the group consisting of a lower alkyl group and a lower alkoxy group; and n is an integer of from 2 to 5. Compound (1) of the present invention and a non-toxic salt thereof have a strong affinity for serotonin 1A receptor and, therefore, they are useful for preventing and treating serotonergic neuron-related diseases, such as motion sickness, space sickness, emesis, dizziness, depression, anxiety, eating disorder, and the like.

This application is a 371 of PCT/JP93/01589 filed Nov. 4, 1993.

1. Technical Field

The present invention relates to novel2-alkoxy-5,6,7,8-tetrahydroquinoxaline derivatives, a production methodthereof, and a pharmaceutical use thereof. The2-alkoxy-5,6,7,8-tetrahydroquinoxaline derivatives are useful forpreventing and treating motion sickness, space sickness, emesis,dizziness, depression, anxiety, eating disorder, and the like.

2. Background Art

It has been known that compounds having an affinity for a serotonin 1Areceptor are useful for preventing and treating motion sickness, spacesickness, emesis, dizziness, depression, anxiety, eating disorder, andthe like. With respect to such compounds, a number of studies have beenmade and the results thereof have been reported [see, "Nippon Rinsho(Japanese Journal of Clinical Medicine)" vol. 47, special edition, pp.1241-1248 (1989); J.P. Feighnev, W.F. Boyer, Psychopathology, 22, 21(1989); P.R. Saxena, C.M. Villalon, TiPS, 11, 95 (1990); N. Matsuki, etal., Jpn. J. Pharmacol. Suppl., 58, 313 (1992); etc.]. On the otherhand, Unexamined Japanese Patent Application Laid-open Specification No.63-107968 discloses 2-[2-(4-substitutedphenyl-1-piperazinyl)ethoxy]-5,6,7,8-tetrahydroquinoxaline derivativeswhich have platelet agglutination suppressive, vasodilative andlipoperoxide formation suppressive activities. In this prior artdocument, however, there is no description with respect to theusefulness of such derivatives for preventing and treating serotonergicneuron-related diseases.

Problems to be Solved by the Invention

It has been desired in the art to develop and provide a compound whichexhibits excellent pharmacological activities against serotonergicneuron-related diseases.

Means for Solving the Problems

In order to solve the above-mentioned problems accompanying the priorart compounds or derivatives, the present inventors have synthesizedvarious types of compounds and have examined the compounds with respectto the pharmacological properties thereof. As a result, it hasunexpectedly been found that 2-alkoxy-5,6,7,8-tetrahydroquinoxalinederivatives represented by formula (1) below, which have never beenreported in any of the literature, exhibit an excellent affinity for aserotonin 1A receptor and excellent pharmacological activities againstserotonergic neuron-related diseases. The present invention has beencompleted, based on the above novel findings.

Accordingly, it is an object of the present invention to provide a novelcompound represented by formula (1) or a non-toxic salt thereof ##STR2##wherein R¹ represents a hydrogen atom or a lower alkyl group; R²represents a pyridyl group which is unsubstituted or substituted with 1to 3 substituents each independently selected from the group consistingof a halogen atom, a lower alkyl group, a tri-fluromethyl group, a loweralkoxy group, a carbamoyl group and a cyano group, or a pyrimidinylgroup which is unsubstituted or substituted with 1 to 2 substituentseach independently selected from the group consisting of a lower alkylgroup and a lower alkoxy group; and n is an integer of from 2 to 5.

It is another object of the present invention to provide a method forproducing the above-mentioned novel compound represented by formula (1)or a non-toxic salt thereof, which comprises reacting, in an inertsolvent, a compound represented by formula (2): ##STR3## wherein R¹ andn are as defined for formula (1) above; and X represents a reactiveleaving group,

with a compound represented by formula (3): ##STR4## wherein R² is asdefined for formula (1) above.

It is a further object of the present invention to provide apharmaceutical composition for treating a serotonergic neuron-relateddisease, which comprises, as an active ingredient, the above-mentionednovel compound represented by formula (1) or a non-toxic salt thereof.

The compound represented by formula (1) of the present invention (whichcompound is hereinafter, frequently referred to as "compound (1)") canbe produced, for example, by reacting, in an inert solvent, a compoundrepresented by formula (2) (which compound is hereinafter, frequentlyreferred to as "compound (2)") with a compound represented by formula(3) (which compound is hereinafter, frequently referred to as "compound(3)").

In formula (2), the lower alkyl group defined by R¹ means a straightchain or branched C₁ -C₆ alkyl group. Examples of lower alkyl groupsinclude methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,pentyl, hexyl, and the like.

The group represented by "X" in formula (2) is a reactive leaving group.In the present specification, the term "reactive leaving group" means agroup which can enhance the reactivity of compound (2) to compound (3)and is adapted to leave compound (2) upon reaction of compound (2) withcompound (3). Examples of reactive leaving groups include a halogenatom, such as a fluorine atom, a chlorine atom, a bromine atom and aniodine atom, and an alkyl- or aryl-sulfonyloxy group, such asmethanesulfonyloxy, benzenesulfonyloxy and p-toluenesulfonyloxy.

Compound (2) is a novel compound, which has not been reported in any ofthe literature. Compound (2) can be produced, for example, by thefollowing sequence of steps:

(a) reacting a compound represented by formula (4) (hereinafter,frequently referred to as "compound (4)"): ##STR5## wherein R¹ is asdefined for formula (1) above with an alkali metal alkoxide (e.g.,sodium methoxide) in an alcohol solvent (e.g., methanol), followed bydistilling-off the alcohol solvent in vacuo from the resultant reactionmixture, or reacting compound (4) with an alkali metal hydride (e.g.,sodium hydride or potassium hydride) in an organic solvent (e.g.,tetrahydrofuran),

thereby obtaining an intermediate compound represented by formula (5)(hereinafter, frequently referred to as "compound (5)"): ##STR6##wherein R¹ is as defined for formula (1) above; and M is an alkali metalatom, such as sodium or potassium;

(b) reacting compound (5) with a compound represented by formula (6)(hereinafter, frequently referred to as "compound (6)"):

    Y-(CH.sub.2).sub.n-1 -COOR.sup.3                           ( 6)

wherein Y represents a halogen atom; R³ represents a lower alkyl group;and n is as defined for formula (1) above in an inert solvent,

thereby obtaining an intermediate compound represented by formula (7)(hereinafter, frequently referred to as "compound (7)"): ##STR7##wherein R¹, R³ and n are as defined for formulae (1) and (6) above;

(c) reacting compound (7) with a reducing agent in an inert solvent,

thereby obtaining an intermediate compound represented by formula (8)(hereinafter, frequently referred to as "compound (8)"): ##STR8##wherein R¹ and n are as defined for formula (1) above; and (d) reactingcompound (8) with a halogenating agent (e.g., thionyl chloride) or asulfonating agent (e.g., methanesulfonyl chloride) in an inert solvent,to thereby convert the hydroxyl group in compound (8) into a reactiveleaving group (X),

thus, obtaining compound (2).

Compound (2) can also be produced via another route, in which theabove-mentioned compound (4) is reacted, in an inert solvent, with acompound represented by formula (9) (hereinafter, frequently referred toas "compound (9)"):

    Y-(CH.sub.2).sub.n -Z                                      (9)

wherein Z represents a halogen atom; and n and Y are as defined forformulae (1) and (6) above, respectively.

Compounds (7) and (8) above are also novel compounds, which have neverbeen reported in any of the literature.

Compound (4), which is used in the above-mentioned reaction, is a knowncompound and is described in Unexamined Japanese Patent ApplicationLaid-open Specification No. 63-107968 and can be synthesized accordingto the process described therein. Compounds (6) and (9) are also knowncompounds and listed in reagent catalogs as commercially availableproducts.

In the reaction for obtaining compound (5) from compound (4), as thealkali metal reagent (alkali metal alkoxide or alkali metal hydride),there can be employed ployed an alkali metal alkoxide, such as lithiummethoxide, sodium methoxide, potassium methoxide, sodium ethoxide,potassium ethoxide or potassium t-butoxide, or an alkali metal hydride,such as lithium hydride, sodium hydride or potassium hydride.

The alkali metal reagent may be used in an equivalent amount to that ofcompound (4). However, the alkali metal reagent is usually used inslight excess relative to the amount of compound (4).

As the solvent to be used in the reaction for obtaining compound (5)from compound (4), an alcohol, such as methanol, ethanol, propanol,butanol or t-butanol, can be employed.

The above-mentioned reaction for obtaining compound (5) can be conductedat a temperature within the range of from -10° C. to room temperature,and usually within the range of from -5° C. to 0° C. The reaction can becompleted within 10 minutes to 1 hour. The amount of the solvent may besuitably selected. For example, the solvent is used in an amount whichis 5 to 100 times the volume amount of compound (4).

Then, compound (5) obtained in the above step is reacted with compound(6) to thereby obtain compound (7). Examples of compound (6) includemethyl and ethyl esters of bromoacetic acid, methyl and ethyl esters ofchloroacetic acid, methyl and ethyl esters of 3-bromo-propionic acid,methyl and ethyl esters of 3-chloropropionic acid, methyl and ethylesters of 4-bromobutyric acid, methyl and ethyl esters of4-chlorobutyric acid, methyl and ethyl esters of 5-bromovaleric acid,methyl and ethyl esters of 5-chlorovaleric acid, and the like.

With respect to the inert solvent to be used in the reaction of compound(5) with compound (6), there is no specific limitation as long as thesolvent does not have an adverse influence on the reaction. As examplesof inert solvents, benzene, toluene, xylene, dimethylformamide,acetonitrile, acetone and t-butyl alcohol can be mentioned. The amountof the inert solvent may be suitably selected. For example, the inertsolvent is used in a volume amount which is 10 to 200 times the volumeamount of compound (6). In the reaction, compound (6) may be used in anequivalent amount to that of compound (5). However, compound (6) isusually used in slight excess relative to the amount of compound (5).

The above-mentioned reaction of compound (5) with compound (6) may beconducted at room temperature or under heating. For example, thereaction is conducted at a temperature within the range of from 50° to120° C. The reaction time may be suitably selected, depending on thetypes of compounds (5) and (6) and the reaction temperature. Thereaction can be terminated upon confirming that a sufficient degree ofreaction for the production of compound (7) has been achieved. Thereaction is usually completed within 1 hour to 1 day.

Then, compound (7) obtained in the above step is reacted with a reducingagent, to thereby obtain compound pound (8). Examples of reducing agentsinclude an alkali metal hydride, such as lithium aluminum hydride. Thereducing agent may be used in an equivalent amount to that of compound(7). However, the reducing agent is usually used in an amount within therange of from 1 to 5 equivalents, preferably 1 to 2 equivalents perequivalent of compound (7).

With respect to the inert solvent to be used in the above-mentionedreducing reaction of compound (7), there is no specific limitation aslong as the solvent does not have an adverse influence on the reaction.Examples of inert solvents include tetrahydrofuran and 1,4-dioxane. Theamount of the inert solvent may be suitably selected. For example, theinert solvent is used in a volume amount which is 10 to 200 times thevolume amount of compound (7).

The above-mentioned reducing reaction of compound (7) may be conductedat a temperature within the range of from -20° C. to room temperature.For example, the reaction is conducted at a temperature within the rangeof from -10° to 10° C. The reaction time may be suitably selected,depending on the reaction temperature and the like. The reaction can beterminated upon confirming that a sufficient degree of reaction for theproduction of compound (8) has been achieved. The reaction is usuallycompleted within 1 hour to 1 day.

Then, compound (8) obtained in the above step is converted into compound(2), in which the hydroxyl group of compound (8) is substituted with ahalogen atom or an alkyl- or arylsulfonyloxy group. This conversionreaction may be conducted in a conventional manner. For example, for theconversion of the hydroxyl group of compound (8) into a halogen atom,compound (8) is reacted with a halogenating agent such as thionylchloride or phosphorus pentachloride.

On the other hand, for the conversion of the hydroxyl group of compound(8) into an alkyl- or aryl-sulfonyloxy group (e.g., methanesulfonyloxy,benzene-sulfonyloxy or p-toluenesulfonyloxy), compound (8) is reactedwith a sulfonating agent, such as an alkyl- or arylsulfonyl chloride(e.g., methanesulfonyl chloride or p-toluenesulfonyl chloride) whichcorresponds to the desired alkyl- or arylsulfonyloxy group.

The above-mentioned conversion reaction of compound (8) to compound (2)can be conducted in an inert solvent, such as methylene chloride orchloroform. The halogenating agent can be used in an amount within therange of from about 1.0 to 1.2 equivalents per equivalent of compound(8). The conversion reaction can be conducted at room temperature orbelow (for example, under ice-cooling) for 1 hour to 1 day. The amountof the solvent may be suitably selected. However, it is preferred to usethe solvent in a volume amount which is 5 to 100 times the volume amountof compound (8).

As mentioned above, compound (2) can also be produced by reactingcompound (4) with compound (9). Examples of compounds (9) include analkane dihalide, such as 1,2-dibromoethane, 1,2-dichloroethane,1-bromo-2-chloroethane, 1,3-dibromopropane, 1,3-dichloropropane,1-bromo-3-chloropropane, 1,4-dibromobutane, 1,4-dichlorobutane,1-bromo-4-chlorobutane, 1,5-dibromopentane, 1,5-dichloropentane,1-bromo-5-chloropentane, and the like.

With respect to the inert solvent to be used in the reaction of compound(4) with compound (9), there is no specific limitation as long as itdoes not have an adverse influence on the reaction. Preferred examplesof inert solvents include benzene, toluene, xylene, dimethylformamide,acetonitrile, acetone and the like. The amount of the inert solvent maybe suitably selected. For example, the inert solvent is used in a volumeamount which is 10 to 200 times the volume amount of compound (4).

It is preferred to conduct the reaction of compound (4) with compound(9) in the presence of a deacidifying agent. The deacidifying agent tobe used can be an inorganic or an organic base. Examples of deacidifyingagents include carbonates, bicarbonates and hydrides of alkali metals,such as potassium carbonate, sodium carbonate, Sodium bicarbonate andsodium hydride; tertiary amines, such as triethylamine, pyridine and1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU); and the like.

In the above-mentioned reaction of compound (4) with compound (9), areaction promoter, such as sodium iodide or potassium iodide, may beadded to the reaction system.

Compound (9) may be used in an equivalent amount to that of compound(4). However, compound (9) is usually used in an amount within the rangeof from 1 to 5 equivalents, preferably 1.2 to 2.0 equivalents perequivalent of compound (4). With respect to the deacidifying agent, theamount to be employed is usually 1 to 2 equivalents per equivalent ofcompound (9).

The reaction of compound (4) with compound (9) can proceed at roomtemperature. However, it is preferred to conduct the reaction byheating, advantageously under reflux of the solvent. The reaction timemay be suitably selected, depending on the types of compounds (4) and(9) and the reaction temperature. The reaction can be terminated uponconfirming that a sufficient degree of reaction for the production ofcompound (2) has been achieved. The reaction is usually completed within1 hour to several days.

Compound (2) thus obtained is reacted with compound (3), to therebyobtain the desired compound represented by formula (1) of the presentinvention. Compound (3) to be used in the reaction is a compoundrepresented by formula (3) above, wherein R² represents a pyridyl groupwhich is unsubstituted or substituted with 1 to 3 substituents eachindependently selected from the group consisting of a halogen atom, alower alkyl group, a trifluoromethyl group, a lower alkoxy group, acarbamoyl group and a cyano group, or a pyrimidinyl group which isunsubstituted or substituted with 1 to 2 substituents each independentlyselected from the group consisting of a lower alkyl group and a loweralkoxy group. Examples of halogen atoms include a fluorine atom, achlorine atom, a bromine atom and an iodine atom. The lower alkyl groupmeans a straight chain or branched C₁ -C₄ alkyl group, such as methyl,ethyl, propyl, isopropyl or butyl group. The lower alkoxy group means astraight chain or branched C₁ -C₄ alkoxy group, such as methoxy, ethoxy,propoxy, isopropoxy or butoxy group.

Compounds (3) are conventionally known compounds, and most of compounds(3) are commercially available. Alternatively, compounds (3) may besynthesized in a conventional manner.

With respect to the inert solvent to be used in the reaction of compound(2) with compound (3), there is no specific limitation as long as itdoes not have an adverse influence on the reaction. Preferred examplesof inert solvents include benzene, toluene, xylene, dimethylformamide,acetonitrile, acetone and the like. The amount of the inert solvent maybe suitably selected. For example, the inert solvent is used in a volumeamount which is 10 to 200 times the volume amount of compound (2).

It is preferred to conduct the reaction of compound (2) with compound(3) in the presence of a deacidifying agent. The deacidifying agent tobe used is an inorganic or organic base. Examples of deacidifying agentsinclude carbonates, bicarbonates and hydrides of alkali metals, such aspotassium carbonate, sodium carbonate, sodium bicarbonate and sodiumhydride; tertiary amines, such as triethylamine, pyridine and1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU); and the like. Compound (3)may be used in an equivalent amount to that of compound (2). However,compound (3) is usually used in an amount within the range of from 1 to5 equivalents, preferably 1.2 to 2.0 equivalents per equivalent ofcompound (2). With respect to the deacidifying agent, the amount to beemployed is usually 1 to 2 equivalents per equivalent of compound (3).

The reaction of compound (2) with compound (3) for obtaining compound(1) can proceed at room temperature. However, it is preferred to conductthe reaction by heating, advantageously under reflux of the solvent. Thereaction time may be suitably selected, depending on the types ofcompounds (2) and (3) and the reaction temperature. The reaction can beterminated upon confirming that a sufficient degree of reaction for theproduction of compound (1) has been achieved, wherein the confirmationis done by thin layer chromatography or high performance liquidchromatography. The reaction is usually completed within 1 hour toseveral days.

Isolation and purification of compound (1) from the reaction mixture ofcompound (2) with compound (3) can be performed by filtrating off theinsoluble substances from the reaction mixture, concentrating thefiltrate, and subjecting the resultant residue to column chromatographyusing silica gel or the like.

In producing intermediates including precursors of compound (2) as wellas compound (2) during the process for the production of the desiredcompound (1) of the present invention, the reaction mixturesrespectively containing the intermediates may be used in situ.Alternatively, compound (2) and the precursors thereof may be isolatedand purified from the respective reaction mixtures. In this case, thepurification of these compounds can be conducted by known methods, suchas column chromatography, using silica gel or the like as a solid phase.

Specific examples of the thus obtained compounds (1) of the presentinvention are enumerated in Table 1.

                  TABLE 1                                                         ______________________________________                                        Py: pyridyl   Pm: pyrimidinyl                                                 each of the numbers shown in parentheses indicates the                        position of substitution with R.sup.2 in pyridyl or pyrimidinyl.              Compound Formula (1)                                                          No.      R.sup.1   n      R.sup.2                                             ______________________________________                                        300      H         4                                                          2-Py                                                                          301      H         4                                                          2-Pm                                                                          409      CH.sub.3  4                                                          2-Py                                                                          410      CH.sub.3  4                                                          2-Pm                                                                          423      C.sub.3 H.sub.7                                                                         4                                                          2-Py                                                                          414      C.sub.3 H.sub.7                                                                         4                                                          2-Pm                                                                          431      iso-C.sub.3 H.sub.7                                                                     4                                                          2-Py                                                                          432      iso-C.sub.3 H.sub.7                                                                     4                                                          2-Pm                                                                          425      C.sub.5 H.sub.11                                                                        4                                                          2-Py                                                                          428      C.sub.5 H.sub.11                                                                        4                                                          2-Pm                                                                          517      H         2                                                          2-Py                                                                          521      H         2                                                          2-Pm                                                                          537      H         3                                                          2-Py                                                                          538      H         3                                                          2-Pm                                                                          511      H         5                                                          2-Py                                                                          512      H         5                                                          2-Pm                                                                          501      H         4                                                          2-Py--CH.sub.3 (6)                                                            502      H         4                                                          2-Py--Cl(3)                                                                   557      H         4                                                          2-Py--OCH.sub.3 (3)                                                           514      H         4                                                          2-Py--CN(3)                                                                   598      H         4                                                          2-Py--(CH.sub.3).sub.2 (3, 6)                                                 500      H         4                                                          2-Py--CH.sub.3 (6)                                                            524      H         4                                                          2-Py--Cl(6)                                                                   526      H         4                                                          2-Py--CONH.sub.2 (3)                                                          539      H         4                                                          2-Py--OCH.sub.3 (6)                                                           561      H         4                                                          2-Py--CN(3)--(CH.sub.3).sub.2 (4, 6)                                          569      H         4                                                          2-Py--(CH.sub.3).sub.2 (4, 6)                                                 621      H         4                                                          2-Py--CF.sub.3 (3)                                                            629      H         4                                                          2-Py--OC.sub.3 H.sub.7 (6)                                                    630      H         4                                                          2-Py--O-iso-C.sub.3 H.sub.7 (6)                                               639      H         4                                                          2-Py--CF.sub.3 (4)                                                            640      H         4                                                          2-Py--CF.sub.3 (6)                                                            481      H         4                                                          2-Pm--(CH.sub.3).sub.2 (4, 6)                                                 504      H         4                                                          2-Pm--CH.sub.3 (4)                                                            549      H         4                                                          2-Pm--(OCH.sub.3).sub.2 (4, 6)                                                562      H         4                                                          2-Pm--OCH.sub.3 (4)--CH.sub.3 (6)                                             ______________________________________                                    

Compound (1) can be provided in the form of a pharmaceuticallyacceptable non-toxic salt thereof, if desired. Examples of non-toxicsalts include salts of inorganic acids, such as hydrochloric acid,sulfuric acid and phosphoric acid; and salts of organic acids, such asacetic acid, propionic acid, tartaric acid, citric acid, glycolic acid,gluconic acid, succinic acid, malic acid, glutamic acid, aspartic acidand methanesulfonic acid.

The above-mentioned non-toxic salts of compound (1) of the presentinvention can be produced using a known method for producing salts fromfree bases. For example, the hydrochloride of compound (1) can beprepared by adding a solution of hydrochloric acid/methanol to compound(1) in an amount of 1 equivalent or more per equivalent of compound (1)to form the hydrochloride of compound (1) as a precipitate, and thencollecting the precipitate. In this instance, when the hydrochloride ofcompound (1) is hardly deposited as a precipitate, an appropriateorganic solvent (e.g., diethyl ether) can be added thereto to depositthe hydrochloride as a precipitate.

Compound (1) and a non-toxic salt thereof thus prepared exhibit a strongaffinity for a serotonin 1A receptor, as mentioned below. Furthermore,the results of animal experiments which are also mentioned below showthat compound (1) and a non-toxic salt thereof are effective fortreating serotonergic neuron-related diseases, such as motion sickness.Thus, it has been confirmed that compound (1) and non-toxic saltsthereof according to the present invention are useful in pharmaceuticalcompositions for treating serotonergic neuron-related diseases. Forpreparation of such a pharmaceutical composition, compound (1) or anon-toxic salt thereof can be combined with a pharmaceuticallyacceptable carrier by a conventional method.

The pharmaceutical composition for treating a serotonergicneuron-related disease according to the present invention may beadministered to a patient orally or parenterally. For parenteraladministration, the pharmaceutical composition can be used, for example,as an injection composition, such as a composition for intravenous drip.The dose of the pharmaceutical composition is varied depending onvarious factors, such as the manner of administration, age, weight,condition of the patient, etc. However, the dose may generally be about0.1 to about 200 mg/kg per day for an adult in terms of the amount ofcompound (1).

The pharmaceutical composition of the present invention can beadministered to a patient in the form of a solution for injection,tablet, pill, powder, granule or capsule. For the preparation of such apharmaceutical composition, various types of pharmaceutically acceptablecarriers can be employed, depending on the form of the pharmaceuticalcomposition. For example, when compound (1) of the present invention isformulated into a medicine for oral administration (such as a tablet,granule, capsule or the like), there can be employed excipients, such asstarch, lactose, refined sugar, mannitol, carboxymethyl cellulose, cornstarch and inorganic salts; binders, such as methylcellulose, sodiumsalt of carboxymethyl cellulose, hydroxypropyl cellulose, crystallinecellulose, ethylcellulose, polyvinyl pyrrolidone and macrogol;disintegrating agents, such as starch, hydroxypropyl starch,carboxymethyl cellulose, sodium carboxymethyl cellulose andhydroxypropyl cellulose; surfactants, such as sodium laurylsulfate,soybean lecithin, sucrose esters of fatty acids and polysorbate 80;lubricants, such as talc, wax, hydrated vegetable oils, sucrose estersof fatty acids, magnesium stearate and calcium stearate; fluiditypromoting agent; sweetening and flavoring agents; and the like.

The pharmaceutical composition of the present invention can beadministered in the form of an emulsion, syrup or elixir.

When compound (1) of the present invention is formulated into a medicinefor parenteral administration, a diluent, such as distilled water forinjection, physiological saline, an aqueous solution of glucose, avegetable oil for injection, propylene glycol or polyethylene glycol,can be used. In addition, if desired, other additives, such as agermicide, antiseptic, stabilizer, isotonicity agent and soothing agent,can be used.

Effect of the Invention

In order to demonstrate the pharmacological activities of compound (1)and a non-toxic salt thereof of the present invention, tests wereconducted with respect to compounds (1) synthesized in Examplesdescribed below. The procedures and results of the tests are as follows.

Each of the compounds (1) used in the following tests was represented bythe number indicated in the corresponding Example, and was tested in theform of a hydrochloride salt thereof.

1. Affinity for serotonin 1A (5HT1A) receptor

(1) Method

(A) Preparation of rat hippocampal membrane fraction

A male SD strain rat (7-week old; Charles River) was decapitated, andbrain was taken out therefrom quickly. 50 mM Tris-HCl buffer (pH 7.4)was added to the brain under ice cooling to obtain a suspension. Theresultant suspension was homogenized, and then subjected tocentrifugation at 48000 g for 15 minutes, to thereby obtain aprecipitate. The precipitate was resuspended in the same Tris-HCl bufferas used above. The resultant suspension was incubated at 30° C. for 20minutes to decompose endogenous serotonin of the rat hippocampalmembrane, followed by centrifugation at 48000 g for 15 minutes tothereby obtain a precipitate. The resultant precipitate was used as arat hippocampal membrane fraction in the following procedures.

(B) Method for the evaluation of the binding ability of ³H-8-hydroxy-dipropylaminotetralin (³ H-8-OH-DPAT) to serotonin 1Areceptor

The rat hippocampal membrane fraction prepared in step (A) above (about100 to 200 μg in terms of proteins) was reacted with 0.5 nM (finalconcentration) ³ H-8-OH-DPAT (which is commercially available fromDuPont-NEN Research Products) and 10 μM (final concentration) pargyline(which is commercially available from Sigma Chemical Company) at 30° C.for 30 minutes to effect a reaction. The resultant reaction mixture wassubjected to suction filtration using a Whatman GF/C filter, to therebyterminate the reaction. The radio-activity of ³ H-8-OH-DPAT adsorbed onthe filter was determined using a liquid scintillation counter. Theobtained value is regarded as a total amount (TB) of specificallybinding ³ H-8-OH-DPAT and non-specifically binding ³ H-8-OH-DPAT.

On the other hand, substantially the same procedure as mentioned abovewas repeated, except that 10 μM (final concentration) serotonin wasadded to the ³ H-8-OH-DPAT and pargyline. The radioactivity of ³H-8-OH-DPAT adsorbed on the filter was determined in the same manner asmentioned above. The obtained value is regarded as the amount (NB) ofnon-specifically binding ³ H-8-OH-DPAT.

Further, substantially the same procedure as mentioned above wasrepeated, except that, instead of serotonin, a test compound was used ina predetermined concentration. The radioactivity of ³ H-8-OH-DPATadsorbed on the filter was determined in the same manner as mentionedabove. The obtained value is regarded as the amount (DTB) of binding ³H-8-OH-DPAT.

(C) Calculation of Ki value

The inhibition ratio of the test compound (at a certain concentration)against the binding of 3H-8-OH-DPAT (the inhibition ratio is hereinafterreferred to simply as "binding inhibition ratio") was calculatedaccording to the following formula:

    Binding inhibition ratio (%)=100-(DTB-NB)÷(TB-NB)×100

With respect to each of the test compounds, the binding inhibitionratios at various concentrations (from a higher concentration to a lowerconcentration) were determined. The binding inhibition ratios wereplotted, taking the logarithmic value of the concentration of testcompound as the abscissa value, and the binding inhibition ratio as theordinate value. Then, a curve was drawn by non-linear least squaremethod. From the curve thus drawn, the IC₅₀ value (the concentration atwhich a test compound inhibits the binding of ³ H-8-OH-DPAT to theserotonin 1A receptor by 50%) was determined with respect to each of thetest compounds.

The Ki value was determined according to the following formula:

    Ki=IC.sub.50 ÷(1+[L]/Kd)

wherein:

[L] is the concentration (0.2 nM) of a radioactive ligand (³H-8-OH-DPAT) used in the test;

Kd is the concentration (0.7174 nM) at which the radioactive ligand (³H-8-OH-DPAT) exhibits the affinity for the serotonin 1A receptor; and

IC₅₀ is the concentration of a test compound at which the test compoundinhibits the binding of the radioactive ligand (³ H-8-OH-DPAT) to theserotonin 1A receptor by 50%.

(2) Results

The Ki values of the individual test compounds to the serotonin 1A(5HT1A) receptor are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Test compound                                                                 (hydrochloride)                                                                              5HT 1A Ki (nM)                                                 ______________________________________                                        300            1.6                                                            301            6                                                              409            16                                                             410            24                                                             537            14                                                             538            25                                                             511            8.4                                                            512            23                                                             501            0.6                                                            502            13                                                             557            1.5                                                            514            4.8                                                            598            25                                                             500            2.1                                                            524            1.9                                                            539            1.3                                                            561            16                                                             569            6.8                                                            629            1.8                                                            630            3                                                              639            11                                                             640            5.2                                                            481            5.3                                                            504            3.9                                                            549            6.6                                                            562            11                                                             ______________________________________                                    

2. Activities against motion sickness

(1) Method

The activities of individual compounds against motion sickness wereexamined using Suncus murinus. Suncus murinus is a small animalbelonging to the Soricidae family. It has been known that suncus islikely to suffer from motion sickness and is susceptible to occurrenceof emesis [see "Seitai-no-kagaku (Science of living body)", 41, 538(1990)]. Suncus is likely to show symptoms like the symptoms of humanmotion sickness under the stimulus of simple acceleration, finallyleading to the occurrence of emesis. It has been recognized that motionsickness is caused by the occurrence of disorder in information, such asvision, equilibrium sense and the like, or by a stimulus which has neverbeen memorized. Further, it has been recognized that the disorder in theinner earvestibular nucleus pathway and the high-order function of braintake part in the occurrence of motion sickness. Therefore, medicinescapable of suppressing the occurrence of emesis of suncus would beuseful for preventing and treating motion sickness, space sickness,emesis, dizziness and the like.

In this test, test compounds were individually administeredintraperitoneally to suncus. 30 minutes after the administration,acceleration-stimulus (amplitude: 4 cm; frequency; 1 Hz) was given tothe suncus, and the suncus thus treated was observed for 10 minutes asto whether emesis occurred or not.

(2) Results

The time for occurrence of emesis was measured with respect to each ofthe test compounds, and the results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                                                            Number                                                         Time for occurrence                                                                          of tested                                 Test compound                                                                             Dose     of emesis      suncus                                    ______________________________________                                        Physiological        1 min. 35 sec. ± 8 sec.                                                                   46                                        saline                                                                        300 (hydrochloride)                                                                       1 mg/kg  Emesis did not occur                                                                         4                                         301 (hydrochloride)                                                                       3 mg/kg  Emesis did not occur                                                                         4                                         501 (hydrochloride)                                                                       1 mg/kg  Emesis did not occur                                                                         4                                         500 (hydrochloride)                                                                       1 mg/kg  Emesis did not occur                                                                         4                                         524 (hydrochloride)                                                                       1 mg/kg  Emesis did not occur                                                                         4                                         539 (hydrochloride)                                                                       1 mg/kg  Emesis did not occur                                                                         4                                         629 (hydrochloride)                                                                       3 mg/kg  Emesis did not occur                                                                         4                                         630 (hydrochloride)                                                                       3 mg/kg  Emesis did not occur                                                                         4                                         504 (hydrochloride)                                                                       1 mg/kg  Emesis did not occur                                                                         4                                         562 (hydrochloride)                                                                       3 mg/kg  Emesis did not occur                                                                         4                                         ______________________________________                                    

As shown in Table 3, with respect to the suncuses to which physiologicalsaline alone have been administered as a control, motion sickness wasinduced with respect to 100% of the suncuses, and emesis occurred within2 minutes from the stimulation. By contrast, with respect to thesuncuses to which the hydrochloride of compound (1) of the presentinvention had been administered, the occurrence of emesis was completelysuppressed. From these results, it is concluded that compounds (1) ofthe present invention are useful for preventing and treating motionsickness, emesis, space sickness, dizziness and the like.

3. Activity to suppress the drug-induced emesis

It has been known that cisplatin and nicotine have an emesis-inducingactivity. In this test, it was investigated as to whether thehydrochloride of compound (1) of the present invention has the activityto suppress the occurrence of emeses which are induced by these drugs.

Cisplatin was intraperitoneally administered to each of four suncuses(20 mg/kg). As a result, with respect to all of the suncuses, emesisoccurred 10 to 20 times within 40 to 70 minutes after the administrationof the cisplatin. However, when compound 300 of the present invention(in the form of the hydrochloride thereof) was intraperitoneallyadministered to the suncuses (0.3 mg/kg) 30 minutes before theadministration of cisplatin, the occurrence of cisplatin-induced emesiswas completely suppressed.

On the other hand, nicotine was subcutaneously administered to foursuncuses (4 mg/kg). As a result, with respect to all of the suncuses,emesis was induced 11 to 29 times within 3 to 10 minutes after theadministration of the nicotine. However, when compound 300 of thepresent invention (in the form of the hydrochloride thereof) wasintraperitoneally administered to the suncuses (3 mg/kg) 30 minutesbefore the administration of nicotine, the occurrence ofnicotine-induced emesis was completely suppressed.

Cisplatin has long been used as a carcinostatic substance. However,there is a serious problem in that cisplatin induces emesis as a sideeffect. Since compound (1) of the present invention can suppress theoccurrence of cisplatin-induced emesis, it is concluded that compound(1) of the present invention is effective for preventing emesis which iscaused by the administration of a carcinostatic substance. At present,it is known that although certain drugs, such as ondansetron (which is a5-HT3 blocking agent), are effective for suppressing cisplatin-inducedemesis, they have no effect on emesis induced by drugs other thancisplatin or on motion sickness. By contrast, as demonstrated above,compound 300 of the present invention (in the form of the hydrochloridethereof) is effective for suppressing nicotine-induced emesis and motionsickness as well as cisplatin-induced emesis and, therefore, compound300 of the present invention can be used as an excellent antiemeticagent for various purposes.

4. Anti-depression activity (which was evaluated by forced swimming testusing rats)

When a rat is put in a water tank, the rat struggles for its life to getout of the water (that is, the rat starts a "forced swimming"). If therat finds that it is impossible for him to get out, the rat stopsswimming and assumes an immobile state. It has been known that theadministration of an antidepressant can cause a violent swimming motionin the rat for getting out of the water, with a result that the timespent in the immobile state is shortened. The shortening of the time inthe immobile state of the rat in the forced swimming test by theadministration of the antidepressant is well correlated to the clinicalanti-depression effect. Accordingly, in developing antidepressants, theforced swimming test using a rat is the most reliable screening method.In the present test, male Wistar strain rats were used. Compound 300 ofthe present invention (in the form of the hydrochloride thereof) wasintraperitoneally administered to a rat. 30 minutes after theadministration, the rat was put in a water tank and then, observed for 6minutes. The time for the rat to keep the immobile state was measured.

As shown in Table 4 below, compound 300 of the present invention (in theform of the hydrochloride thereof; 1 mg/kg and 10 mg/kg) remarkablyshortened the time for the rat to keep the immobile state. From theseresults, it is concluded that compound 300 of the present invention iseffective for preventing and treating depression.

                  TABLE 4                                                         ______________________________________                                                             Time spent in                                                                              Number of                                   Test compound                                                                             Dose     immobile state                                                                             tested rats                                 ______________________________________                                        Physiological saline                                                                           236 sec.     8                                               (control)                                                                     300 (hydrochloride)                                                                        1 mg/kg 173 sec.     6                                                       10 mg/kg 163 sec.     6                                           ______________________________________                                    

Further, when each of compounds (1) of the present invention synthesizedin Examples (each in the form of the hydrochloride thereof) wasintraperitoneally administered to three mice (50 mg/kg), none of themice died. The results indicate that compounds (1) of the presentinvention are highly safe.

From the above results, it will be understood that compound (1) of thepresent invention (in the form of the hydrochloride thereof) has astrong affinity for the serotonin 1A receptor, and are useful forprevention and treatment of a serotonergic neuron-related disease, suchas motion sickness, space sickness, emesis, dizziness, depression,anxiety, eating disorder or the like.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in greater detail with referenceto the following Reference Examples and Examples, in respect of desiredcompounds (1) and hydrochlorides thereof, production methods thereof,and intermediates for the synthesis of compounds (1).

Physical properties (i.e., NMR spectra and mass spectra) of thecompounds obtained in the following Reference Examples and Examples areshown in Tables 9 and 10 below.

Reference Example 1 2-Hydroxy-5,6,7,8-tetrahydroquinoxaline

11.05 g (0.1 mol) of glycinamide hydrochloride was dissolved in 200 mlof methanol. To the resultant solution was added a solution of 13.44 g(0.12 mol) of cyclohexane-1,2-dione in 30 ml of methanol under coolingto -30° C. or lower and then, 20 ml of an aqueous 12.5 N NaOH solutionwas dropwise added thereto. Subsequently, the resultant mixture wasstirred at -30° C. or lower for 30 minutes and further stirred at roomtemperature for 3 hours to effect a reaction. To the resultant reactionmixture was added 25 ml of concentrated hydrochloric acid, followed bystirring for 10 minutes and then, 15 g of sodium hydrogencarbonate wasadded thereto. The solvent of the reaction mixture was distilled off invacuo to thereby obtain a residue. Water was added-to the obtainedresidue, followed by extraction with chloroform three times to obtain anextract. The extract was dried over anhydrous magnesium sulfate andconcentrated in vacuo. The resultant residue was recrystallized fromacetone, to thereby obtain 9.36 g of2-hydroxy-5,6,7,8-tetrahydroquinoxaline (yield: 62.4%).

Reference Example 22-(3-Ethoxycarbonylpropoxy)-5,6,7,8-tetrahydroquinoxaline

1.5 g (10 mmol) of 2-hydroxy-5,6,7,8-tetrahydroquinoxaline was dissolvedin 30 ml of methanol. To the resultant solution was added 10 ml of a 1Nsolution of sodium methoxide in methanol to effect a reaction. Thesolvent of the resultant reaction mixture was distilled off in vacuo tothereby obtain a sodium salt of 2-hydroxy-5,6,7,8-tetrahydroquinoxaline.The sodium salt was dissolved in 30 ml of N,N-dimethylformamide (DMF),and 1.95 g (10 mmol) of ethyl 4-bromobutyrate was added thereto. Theresultant mixture was stirred with heating at 100° C. overnight toeffect a reaction. The solvent of the resultant reaction mixture wasdistilled off in vacuo to thereby obtain a residue. Water was added tothe obtained residue, followed by extraction with chloroform twice toobtain an extract. The extract was dried over mirabilite, and thesolvent was distilled off to thereby obtain a residue. The obtainedresidue was purified by silica gel column chromatography. That is, theresidue was charged in a column of 40 g of silica gel (C-200,manufactured and sold by Wako Pure Chemical Industries, Ltd.) and elutedwith toluene-ethyl acetate (10:1), to thereby obtain 1.59 g of2-(3-ethoxycarbonylpropoxy)-5,6,7,8-tetrahydroquinoxaline (yield:60.3%).

Reference Examples 3 to 63-Alkyl-2-(3-ethoxycarbonylpropoxy)-5,6,7,8-tetrahydroquinoxalines

Substantially the same procedure as in Reference Example 2 was repeatedexcept that four types of3-alkyl-2-hydroxy-5,6,7,8-tetrahydroquinoxalines were individually usedinstead of 2-hydroxy-5,6,7,8-tetrahydroquinoxaline, to thereby obtainfour types of3-alkyl-2-(3-ethoxycarbonylpropoxy)-5,6,7,8-tetrahydroquinoxalinescorresponding thereto. The amounts of the3-alkyl-2-hydroxy-5,6,7,8-tetrahydroquinoxalines used are shown in Table5, together with the amounts and yields of the desired3-alkyl-2-(3-ethoxycarbonylpropoxy)-5,6,7,8-tetrahydroquinoxalinesproduced.

                  TABLE 5                                                         ______________________________________                                         ##STR9##                                                                                       Amount of 2-*.sup.1)                                        Reference         hydroxy      Product                                        Example           compound used                                                                              Amount Yield                                   No.      R.sup.1  (g)          (g)    (%)                                     ______________________________________                                        3        CH.sub.3 1.64         1.73   62.1                                    4        C.sub.3 H.sub.7                                                                        2.30         2.13   58.0                                    5        iso-C.sub.3 H.sub.7                                                                    2.30         1.91   52.0                                    6        C.sub.5 H.sub.11                                                                       2.20         2.31   69.2                                    ______________________________________                                         *.sup.1) Note: 2hydroxy compound means a                                      3alkyl-2-hydroxy-5,6,7,8-tetrahydroquinoxaline.                          

Reference Example 7 2-(4-Hydroxybutoxy)-5,6,7,8-tetrahydroquinoxaline

1.84 g (7.0 mmol) of2-(3-ethoxycarbonylpropoxy)-5,6,7,8-tetrahydroquinoxaline was dissolvedin 10 ml of tetrahydrofuran (THF), and the solution was ice-cooled. Theresultant solution was dropwise added to a suspension of 319 mg (8.4mmol) of lithium aluminum hydride in 15 ml of THF under ice cooling,followed by stirring for 2 hours at the same temperature as used in theice cooling above, to thereby effect a reaction. To the resultantreaction mixture was added 2N HCl to thereby acidify the mixture andform a precipitate. The resultant mixture was subjected to filtration tofilter off the precipitate, which was then washed with water. Thefiltrate was extracted with chloroform twice to obtain an extract. Theextract was dried over mirabilite, and the solvent was distilled off invacuo. The resultant residue was purified by silica gel columnchromatography. That is, the residue was charged in a column of 50 g ofsilica gel (C-200, manufactured and sold by Wako Pure ChemicalIndustries, Ltd.) and eluted with chloroform-methanol (200:1), tothereby obtain 1.55 g of2-(4-hydroxybutoxy)-5,6,7,8-tetrahydroquinoxaline (yield: 100%).

Reference Examples 8 to 113-Alkyl-2-(4-hydroxybutoxy)-5,6,7,8-8-tetrahydroquinoxalines

Substantially the same procedure as in Reference Example 7 was repeatedexcept that four types of3-alkyl-2-(3-ethoxycarbonylpropoxy)-5,6,7,8-tetrahydroquinoxalines wereindividually used instead of2-(3-ethoxycarbonylpropoxy)-5,6,7,8-tetrahydroquinoxaline, to therebyobtain four types of3-alkyl-2-(4-hydroxybutoxy)-5,6,7,8-tetrahydroquinoxalines correspondingthereto.

The amounts of the3-alkyl-2-(3-ethoxycarbonylpropoxy)-5,6,7,8-tetrahydroquinoxalines usedare shown in Table 6, together with the amounts and yields of thedesired 3-alkyl-2-(4-hydroxybutoxy)-5,6,7,8-tetrahydroquinoxalinesproduced.

                  TABLE 6                                                         ______________________________________                                         ##STR10##                                                                                      Amount of*.sup.2)                                           Reference         ester        Product                                        Example           compound used                                                                              Amount Yield                                   No.      R.sup.1  (g)          (g)    (%)                                     ______________________________________                                        8        CH.sub.3 1.56         1.32   100                                     9        C.sub.3 H.sub.7                                                                        1.98         1.44   82.4                                    10       iso-C.sub.3 H.sub.7                                                                    2.14         1.83   97.8                                    11       C.sub.5 H.sub.11                                                                       1.78         1.51   98.3                                    ______________________________________                                         *.sup.2) Note: Ester compound means a                                         3alkyl-2-(3-ethoxy-carbonylpropoxy)-5,6,7,8-tetrahydroquinoxaline.       

Reference Example 122-(4-Methanesulfonyloxybutoxy)-5,6,7,8-tetrahydroquinoxaline

1.55 g (6.98 mmol) of 2-(4-hydroxybutoxy)-5,6,7,8-tetrahydroquinoxalinewas dissolved in 30 ml of methylene chloride, and the solution wasice-cooled. To the resultant solution was added 1.17 ml (8.4 mmol) oftriethylamine and then, 0.59 ml (7.7 mmol) of methanesulfonyl chloridewas dropwise added thereto. The resultant mixture was stirred for 2.5hours at the same temperature as used in the ice cooling above, tothereby by effect a reaction. To the resultant reaction mixture wasadded 20 ml of chloroform to obtain a mixture. The mixture was extractedwith an aqueous solution of diluted sodium carbonate to thereby obtainan organic layer and an aqueous layer. The aqueous layer was subjectedto extraction with chloroform to obtain an additional organic layer. Thetwo organic layers were combined and dried over mirabilite and then, thesolvent of the resultant organic layer was distilled off in vacuo, tothereby obtain 1.92 g of2-(4-methanesulfonyloxybutoxy)-5,6,7,8-tetrahydroquinoxoline (yield:91.7%).

Reference Examples 13 to 163-Alkyl-2-(4-methanesulfonyloxybutoxy)-5,6,7,8-tetrahydroquinoxalines

Substantially the same procedure as in Reference Example 12 was repeatedexcept that four types of3-alkyl-2-(4-hydroxybutoxy)-5,6,7,8-tetrahydroquinoxlines wereindividually used instead of2-(4-hydroxybutoxy)-5,6,7,8-tetrahydroquinoxaline, to thereby obtainfour types of3-alkyl-2-(4-methanesulfonyloxybutoxy)-5,6,7,8-tetrahydroquinoxalinescorresponding thereto. The amounts of the3-alkyl-2-(4-hydroxybutoxy)-5,6,7,8-tetrahydroquinoxalines used areshown in Table 7, together with the amounts and yields of the desired3-alkyl-2-(4-methanesulfonyloxybutoxy)-5,6,7,8-tetrahydroquinoxalinesproduced.

                  TABLE 7                                                         ______________________________________                                         ##STR11##                                                                                      Amount of*.sup.3)                                           Reference         hydroxy      Product                                        Example           compound used                                                                              Amount Yield                                   No.      R.sup.1  (g)          (g)    (%)                                     ______________________________________                                        13       CH.sub.3 1.47         1.74   89.1                                    14       C.sub.3 H.sub.7                                                                        1.30         1.59   94.1                                    15       iso-C.sub.3 H.sub.7                                                                    1.43         1.86   100                                     16       C.sub.5 H.sub.11                                                                       1.68         1.99   93.4                                    ______________________________________                                         *.sup.3) Note: Hydroxy compound means a                                       3alkyl-2-(4-hydroxybutoxy)-5,6,7,8-tetrahydroquinoxaline.                

Reference Example 17 2-(4-Chlorobutoxy)-5,6,7,8-tetrahydroquinoxaline

300 mg (2 mmol) of 2-hydroxy-5,6,7,8-tetrahydroquinoxaline was dissolvedin 5 ml of DMF, and 360 μl (2.4 mmol) of1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) and 277 μl (2.4 mmol) of1-bromo-4-chlorobutane were added thereto. The resultant mixture wasstirred with heating at 60° C. for 22 hours to effect a reaction. TheDMF in the resultant reaction mixture was distilled off in vacuo tothereby obtain a residue. An aqueous solution of potassium carbonate wasadded to the obtained residue, followed by extraction with chloroform toobtain an extract. The extract was dried over sodium sulfate anhydride,and subjected to filtration to thereby obtain a filtrate. The solvent ofthe filtrate was distilled off to thereby obtain a residue. The obtainedresidue was purified by silica gel column chromatography. That is, theresidue was charged in a column of 20 g of silica gel (Art7734,manufactured and sold by E. Merck, Darmstadt) and eluted withchloroform, to thereby obtain 263 mg of2-(4-chlorobutoxy)-5,6,7,8-tetrahydroquinoxaline (yield: 54.7%).

Reference Example 182-(4-Chlorobutoxy)-3-isopropyl-5,6,7,8-tetrahydroquinoxaline

Substantially the same procedure as in Reference Example 17 was repeatedexcept that 384 mg (2 mmol) of2-hydroxy-3-isopropyl-5,6,7,8-tetrahydroquinoxaline was used instead of2-hydroxy-5,6,7,8-tetrahydroquinoxaline, to thereby obtain 287 mg of2-(4-chlorobutoxy)-3-isopropyl-5,6,7,8-tetrahydroquinoxaline (yield:50.8%).

Reference Example 192-Ethoxycarbonylmethoxy-5,6,7,8-tetrahydroquinoxaline

Substantially the same procedure as in Reference Example 2 was repeatedexcept that 1.67 g (10 mmol) of ethyl bromoacetate was used instead ofethyl 4-bromobutyrate, to thereby obtain 4.04 g of2-ethoxycarbonyl-methoxy-5,6,7,8-tetrahydroquinoxaline (yield: 86%).

Reference Example 20 2-(2-Hydroxyethoxy)-5,6,7,8-tetrahydroquinoxaline

Substantially the same procedure as in Reference Example 7 was repeatedexcept that 1.65 g (7 mmol) of2-ethoxycarbonylmethoxy-5,6,7,8-tetrahydroquinoxaline was used insteadof 2-(3-ethoxycarbonylpropoxy)-5,6,7,8-tetrahydroquinoxaline, to therebyobtain 0.95 g of 2-(2-hydroxyethoxy)-5,6,7,8-tetrahydroquinoxaline(yield: 70%).

Reference Example 21 2-(3-Chloropropoxy)-5,6,7,8-tetrahydroquinoxaline

1.5 g (10 mmol) of 2-hydroxy-5,6,7,8-tetrahydroquinoxaline was dissolvedin 40 ml of acetonitrile. To the resultant solution were added 2.76 g(20 mmol) of potassium carbonate and 1.19 ml (12 mmol) of1-bromo-3-chloropropane. The resultant mixture was heated under refluxfor 2 hours and then, subjected to filtration to thereby filter offinsoluble substances. The solvent of the filtrate was distilled off invacuo to thereby obtain a residue. The obtained residue was purified bysilica gel column chromatography. That is, the residue was charged in acolumn of 42 g of silica gel (Art7734, manufactured and sold by E.Merck, Darmstadt) and eluted with chloroform, to thereby obtain 1.47 gof 2-(3-chloropropoxy)-5,6,7,8-tetrahydroquinoxaline (yield: 67%).

Reference Example 22 2-(5-Chloropentoxy)-5,6,7,8-tetrahydroquinoxaline

Substantially the same procedure as in Reference Example 21 was repeatedexcept that 1.58 ml (12 mmol) of 1-bromo-5-chloropentane was usedinstead of 1-bromo-3-chloropropane, to thereby obtain 2.46 g of2-(5-chloropentoxy)-5,6,7,8-tetrahydroquinoxaline (yield: 97%).

EXAMPLE 12-[4-{4-(2-Pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 300)

300 mg (1 mmol) of2-(4-methanesulfonyloxybutoxy)-5,6,7,8-tetrahydroquinoxaline wasdissolved in 10 ml of acetonitrile. To the resultant solution were added208 mg (1.5 mmol) of potassium carbonate and 196 mg (1.2 mmol) of1-(2-pyridyl)piperazine, and the resultant mixture was heated underreflux for 15 hours. Then, the mixture was subjected to filtration tofilter off insoluble substances, which were then washed withacetonitrile, to thereby obtain a filtrate. The solvent of the filtratewas distilled off in vacuo to thereby obtain a residue. The obtainedresidue was purified by silica gel column chromatography. That is, theresidue was charged in a column of 20 g of silica gel (Art7734,manufactured and sold by E. Merck, Darmstadt) and eluted withchloroform-methanol (100:1), to thereby obtain 293 mg of2-[4-{4-(2-pyridyl)-1-piperazinyl}-butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 300) (yield: 79.8%).

The obtained2-[4-{4-(2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas dissolved in a solution of 8.9N hydrochloric acid in methanol. Tothe resultant solution was added diethyl ether, to thereby crystallize asolid substance in the solution. The resultant solution was subjected tofiltration, to thereby obtain the hydrochloride of2-[4-{4-(2-pyridyl)-1piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline.

EXAMPLE 22-[4-{4-(2-Pyrimidinyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 301)

Substantially the same procedure as in Example 1 was repeated, exceptthat 197 mg (1.2 mmol) of 1-(2-pyrimidinyl)piperazine was used insteadof 1-(2-pyridyl)piperazine, to thereby obtain 158 mg of2-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 301) (yield: 42.9%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLES 3 to 102-[4-{4-(2-Pyridyl)-1-piperazinyl}butoxy]-3-alkyl-5,6,7,8-tetrahydroquinoxalinesand2-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butoxy]-3-alkyl-5,6,7,8-tetrahydroquinoxalines(compounds 409, 410, 423, 414, 431, 432, 425 and 428)

Substantially the same procedures as in Examples 1 and 2 were repeated,in which the four types of2-(4-methanesulfonyloxybutoxy)-3-alkyl-5,6,7,8-tetrahydroquinoxalineswere used instead of2-(4-methanesulfonyloxybutoxy)-5,6,7,8-tetrahydroquinoxalines, andreacted with each of 1-(2-pyridyl)piperazine and1-(2-pyrimidinyl)piperazine, to thereby obtain four types of2-[4-{4-(2-pyridyl)-1-piperazinyl}butoxy]-3-alkyl-5,6,7,8-tetrahydroquinoxalinesand four types of2-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butoxy]-3-alkyl-5,6,7,8-tetrahydroquinoxalines(compounds 409, 410, 423, 414, 431, 432, 435 and 428) correspondingthereto.

The hydrochlorides of the obtained2-[4-{4-(2-pyridyl)-1-piperazinyl}butoxy]-3-alkyl-5,6,7,8-tetrahydroquinoxalinesand2-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butoxy]-3-alkyl-5,6,7,8-tetrahydroquinoxalineswere obtained in the same manner as in Example 1.

The amounts of the 3-alkylated compounds (2')[2-(4-methanesulfonyloxybutoxy)-3-alkyl-5,6,7,8-tetrahydroquinoxalines]and piperazine derivatives (3) [1-(2-pyridyl)piperazine and1-(2-pyrimidinyl)piperazine] used are shown in Table 8, together withthe amounts and yields of the desired2-[4-{4-(2-pyridyl)-1-piperazinyl}butoxy]-3-alkyl-5,6,7,8-tetrahydroquinoxalinesand2-[4-{4-(2-pyrimidinyl)-1-piperazinyl}butoxy]-3-alkyl-5,6,7,8-tetrahydroquinoxalinesproduced.

                  TABLE 8                                                         ______________________________________                                         ##STR12##                                                                    3-alkylated   Piperazine  Desired compound                                    compound      derivative  (1')                                                Ex-   (2')        (3)         Com-                                            ample R.sup.1     R.sup.2     pound Amount (mg)                               No.   (Amount used)                                                                             (Amount used)                                                                             No.   Yield (%)                                 ______________________________________                                        3     CH.sub.3    2-pyridyl   409   327 mg                                          (314 mg)    (196 mg)          85.7%                                     4     CH.sub.3    2-pyrimidinyl                                                                             410   361 mg                                          (314 mg)    (197 mg)          94.5%                                     5     C.sub.3 H.sub.7                                                                           2-pyridyl   423   384 mg                                          (342 mg)    (196 mg)          93.9%                                     6     C.sub.3 H.sub.7                                                                           2-pyrimidinyl                                                                             414   383 mg                                          (342 mg)    (197 mg)          93.3%                                     7     iso-C.sub.3 H.sub.7                                                                       2-pyridyl   431   375 mg                                          (342 mg)    (196 mg)          91.6%                                     8     iso-C.sub.3 H.sub.7                                                                       2-pyrimidinyl                                                                             432   406 mg                                          (342 mg)    (197 mg)          99.1%                                     9     C.sub.5 H.sub.11                                                                          2-pyridyl   425   389 mg                                          (370 mg)    (196 mg)          89.1%                                     10    C.sub.5 H.sub.11                                                                          2-pyrimidinyl                                                                             428   413 mg                                          (370 mg)    (197 mg)          94.4%                                     ______________________________________                                    

EXAMPLE 112-[4-{4-(2-Pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 300).

Substantially the same procedure as in Example 1 was repeated, exceptthat 241 mg (1 mmol) of 2-(4-chlorobutoxy)-5,6,7,8-tetrahydroquinoxalinewas used instead of2-(4-methanesulfonyloxybutoxy)-5,6,7,8-tetrahydroquinoxaline, and that149 mg (1 mmol) of sodium iodide was added thereto, to thereby obtain148 mg of2-[4-{4-(2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 300) (yield: 40.4%).

EXAMPLE 122-[4-{4-(4,6-Dimethyl-2-pyrimidinyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 481)

241 mg (1 mmol) of 2-(4-chlorobutoxy)-5,6,7,8-tetrahydroquinoxaline wasdissolved in 10 ml of acetonitrile. To the resultant solution were added208 mg (1.5 mmol) of potassium carbonate and 230 mg (1.2 mmol) of1-(4,6-dimethyl-2-pyrimidinyl)piperazine, and the resultant mixture washeated under reflux for 15 hours. Then, the mixture was subjected tofiltration to filter off insoluble substances, which were then washedwith acetonitrile, to thereby obtain a filtrate. The solvent of thefiltrate was distilled off in vacuo to thereby obtain a residue. Theobtained residue was purified by silica gel column chromatography. Thatis, the residue was charged in a column of 20 g of silica gel (Art7734,manufactured and sold by E. Merck, Darmstadt) and eluted withchloroform-methanol (100:1), to thereby obtain 191 mg of2-[4-{4-(4,6-dimethyl-2-pyrimidinyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 481) (yield: 48.2%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(4,6-dimethyl2-pyrimidinyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 13 2-[4-{4-(6-Methyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline (compound 501)

241 mg (1 mmol) of 2-(4-chlorobutoxy)-5,6,7,8-tetrahydroquinoxaline wasdissolved in 10 ml of acetonitrile. To the resultant solution were added208 mg (1.5 mmol) of potassium carbonate, 212 mg (1.2 mmol) of1-(6-methyl-2-pyridyl)piperazine and 149 mg (1 mmol) of sodium iodide,and the resultant mixture was heated under reflux for 15 hours. Then,the mixture was subjected to filtration to filter off insolublesubstances, which were then washed with acetonitrile, to thereby obtaina filtrate. The solvent of the filtrate was distilled off in vacuo tothereby obtain a residue. The obtained residue was purified by silicagel column chromatography. That is, the residue was charged in a columnof 20 g of silica gel (Art7734, manufactured and sold by E. Merck,Darmstadt) and eluted with chloroform-methanol (100:1), to therebyobtain 129 mg of2-[4-{4-(6-methyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 501) (yield: 34%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(6-methyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 142-[4-{4-(3-Chloro-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 502)

Substantially the same procedure as in Example 13 was repeated, exceptthat 237 mg (1.2 mmol) of 1-(3-chloro-2-pyridyl)piperazine was usedinstead of 1-(6-methyl-2-pyridyl)piperazine, to thereby obtain 171 mg of2-[4-{4-(3-chloro-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline (compound 502) (yield: 45%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(3-chloro-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 152-[4-{4-(3-Methoxy-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 557),

Substantially the same procedure as in Example 13 was repeated, exceptthat 232 mg (1.2 mmol) of 1-(3-methoxy-2-pyridyl)piperazine was usedinstead of 1-(6-methyl-2-pyridyl)piperazine, to thereby obtain 179 mg of2-[4-{4-(3-methoxy-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 557) (yield: 45%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(3-methoxy-2-pyridyl-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 162-[4-{4-(3-Cyano-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 514)

Substantially the same procedure as in Example 13 was repeated, exceptthat 226 mg (1.2 mmol) of 1-(3-cyano-2pyridyl)piperazine was usedinstead of 1-(6-methyl-2-pyridyl)piperazine, to thereby obtain 309 mg of2-[4-{4-(3-cyano-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 514) (yield: 79%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(3-cyano-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 172-[4-{4-(3,6-Dimethyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 598)

Substantially the same procedure as in Example 13 was repeated, exceptthat 229 mg (1.2 mmol) of 1-(3,6-dimethyl-2-pyridyl)piperazine was usedinstead of 1-(6-methyl-2-pyridyl)piperazine, to thereby obtain 113 mg of2-[4-{4-(3,6-dimethyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 598) (yield: 30%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(3,6-dimethyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 182-[4-{4-(6-Chloro-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 500)

Substantially the same procedure as in Example 13 was repeated, exceptthat 237 mg (1.2 mmol) of 1-(6-chloro-2-pyridyl)piperazine was usedinstead of 1-(6-methyl-2-pyridyl)piperazine, to thereby obtain 108 mg of2-[4-{4-(6-chloro-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 500) (yield: 27%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(6-chloro-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 192-[4-{4-(6-Ethoxy-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 524)

Substantially the same procedure as in Example 13 was repeated, exceptthat 248 mg (1.2 mmol) of 1-(6-ethoxy-2-pyridyl)piperazine was usedinstead of 1-(6-methyl-2-pyridyl)piperazine, to thereby obtain 282 mg of2-[4-{4-(6-ethoxy-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 524) (yield: 69%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(6-ethoxy-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 202-[4-{4-(3-Carbamoyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(Compound 526)

Substantially the same procedure as in Example 13 was repeated, exceptthat 245 mg (1.2 mmol) of 1-(3-carbamoyl-2-pyridyl)piperazine was usedinstead of 1-(6-methyl-2-pyridyl)piperazine, to thereby obtain 302 mg of2-[4-{4-(3-carbamoyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 526) (yield: 74%).

In substantially the same manner in Example 1, the hydrochloride of theobtained2-[4-{4-(3-carbamoyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 212-[4-{4-(6-Methoxy-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 539)

Substantially the same procedure as in Example 13 was repeated, exceptthat 232 mg (1.2 mmol) of 1-(6-methoxy-2-pyridyl)piperazine was usedinstead of 1-(6-methyl-2-pyridyl)piperazine, to thereby obtain 336 mg of2-[4-{4-(6-methoxy-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 539) (yield: 85%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(6-methoxy-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 222-[4-{4-(3-Cyano-4-6-dimethyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 561)

Substantially the same procedure as in Example 13 was repeated, exceptthat 259 mg (1.2 mmol) of 1-(3-cyano-4,6-dimethyl-2-pyridyl)piperazinewas used instead of 1-(6-methyl-2-pyridyl)piperazine, to thereby obtain192 mg of2-[4-{4-(3-cyano-4,6-dimethyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 561) (yield: 46%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(3-cyano-4,6-dimethyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 232-[4-{4-(4,6-Dimethyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 569)

Substantially the same procedure as in Example 13 was repeated, exceptthat 229 mg (1.2 mmol) of 1-(4,6-dimethyl-2-pyridyl)piperazine was usedinstead of 1-(6-methyl-2-pyridyl)piperazine, to thereby obtain 216 mg of2-[4-{4-(4,6-dimethyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 569) (yield: 66%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(4,6-dimethyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 242-[4-{4-(3-Trifluoromethyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 621)

Substantially the same procedure as in Example 13 was repeated, exceptthat 277 mg (1.2 mmol) of 1-(3-trifluoromethyl-2-pyridyl)piperazine wasused instead of 1-(6-methyl-2-pyridyl)piperazine, to thereby obtain 359mg of2-[4-{4-(3-trifluoromethyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 621) (yield: 83%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(3-trifluoromethyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 252-[4-{4-(6-Propoxy-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 629)

Substantially the same procedure as in Example 13 was repeated, exceptthat 265 mg (1.2 mmol) of 1-(6-propoxy-2-pyridyl)piperazine was usedinstead of 1-(6-methyl-2-pyridyl)piperazine, to thereby obtain 257 mg of2-[4-{4-(6-propoxy-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 629) (yield: 61%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(6-propoxy-2-pyridyl)-1-peperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 262-[4-{4-(6-Isopropoxy-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 630)

Substantially the same procedure as in Example 13 was repeated, exceptthat 265 mg (1.2 mmol) of 1-(6-isopropoxy-2-pyridyl)piperazine was usedinstead of 1-(6-methyl-2pyridyl)piperazine, to thereby obtain 148 mg of2-[4-{4-(6-isopropoxy-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 630) (yield: 35%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(6-isopropoxy-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 272-[4-{4-(4-Trifluoromethyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 639)

Substantially the same procedure as in Example 13 was repeated, exceptthat 277 mg (1.2 mmol) of 1-(4-trifluoromethyl-2-pyridyl)piperazine wasused instead of 1-(6-methyl-2-pyridyl)piperazine, to thereby obtain 283mg of2-[4-{4-(4-trifluoromethyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 639) (yield: 65%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(4-trifluoromethyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 282-[4-{4-(6-Trifluoromethyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 640)

Substantially the same procedure as in Example 13 was repeated, exceptthat 277 mg (1.2 mmol) of 1-(6-trifluoromethyl-2-pyridyl)piperazine wasused instead of 1-(6-methyl-2-pyridyl)piperazine, to thereby obtain 281mg of2-[4-{4-(6-trifluoromethyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 640) (yield: 65%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(6-trifluoromethyl-2-pyridyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 292-[4-{4-(4-Methyl-2-pyrimidinyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 504)

Substantially the same procedure as in Example 13 was repeated, exceptthat 214 mg (1.2 mmol) of 1-(4-methyl-2-pyrimidinyl)piperazine was usedinstead of 1-(6-methyl-2-pyridyl)piperazine, to thereby obtain 174 mg of2-[4-{4-(4-methyl-2-pyrimidinyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 504) (yield: 45%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(4-methyl-2-pyrimidinyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 302-[4-{4-(4,6-Dimethoxy-2-pyrimidinyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 549)

Substantially the same procedure as in Example 13 was repeated, exceptthat 269 mg (1.2 mmol) of 1-(4,6-dimethoxy-2-pyrimidinyl)piperazine wasused instead of 1-(6-methyl-2-pyridyl)piperazine, to thereby obtain 171mg of2-[4-{4-(4,6-dimethoxy-2-pyrimidinyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 549) (yield: 40%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(4,6-dimethoxy-2-pyrimidinyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 312-[4-{4-(4-Methoxy-6-methyl-2-pyrimidinyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 562)

Substantially the same procedure as in Example 13 was repeated, exceptthat 250 mg (1.2 mmol) of 1-(4-methoxy-6-methyl-2-pyrimidinyl)piperazinewas used instead of 1-(6-methyl-2-pyridyl)piperazine, to thereby obtain373 mg of2-[4-{4-(4-methoxy-6-methyl-2-pyrimidinyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxaline(compound 562) (yield: 90%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[4-{4-(4-methoxy-6-methyl-2-pyrimidinyl)-1-piperazinyl}butoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 322-[2-{4-(2-Pyridyl)-1-piperazinyl}ethoxy]-5,6,7,8-tetrahydroquinoxaline(compound 517)

291 mg (1.5 mmol) of 2-(2-hydroxyethoxy)-5,6,7,8-tetrahydroquinoxalinewas dissolved in 15 ml of methylene chloride. To the resultant solutionwas added 0.25 ml (1.8 mmol) of triethylamine and then, 0.13 ml (1.65mmol) of methanesulfonyl chloride was added dropwise thereto. Theresultant mixture was stirred at room temperature for 2.5 hours toeffect a reaction. To the resultant reaction mixture was addedchloroform to obtain a mixture. The mixture was extracted with anaqueous potassium carbonate solution to thereby obtain an organic layerand an aqueous layer. The aqueous layer was subjected to extraction withchloroform to obtain an additional organic layer. The two organic layerswere combined, dried over sodium sulfate, and subjected to filtration,followed by concentration, to thereby obtain 408 mg of2-(2-methanesulfonyloxyethoxy) -5,6,7,8-tetrahydroquinoxaline. The thusobtained 2-(2-methanesulfonyloxyethoxy)-5,6,7,8-tetrahydroquinoxalinewas dissolved in 10 ml of acetonitrile. To the resultant solution wereadded 0.31 g (2.25 mmol) of potassium carbonate and 294 mg (1.8 mmol) of1-(2-pyridyl)piperazine, and the resultant mixture was heated underreflux for 24 hours. Then, the mixture was subjected to filtration tofilter off insoluble substances, which were then washed withacetonitrile, to thereby obtain a filtrate. The solvent of the filtratewas distilled off in vacuo to thereby obtain a residue. The obtainedresidue was purified by silica gel column chromatography. That is, theresidue was charged in a column of 20 g of silica gel (Art7734,manufactured and sold by E. Merck, Darmstadt) and eluted withchloroform-methanol (100:1), to thereby obtain 522 mg of2-[2-{4-(2-pyridyl)-1-piperazinyl}ethoxy]-5,6,7,8-tetrahydroquinoxaline(compound 517) (yield: 100%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[2-{4-(2-pyridyl)-1-piperazinyl}ethoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 332-[2-{4-(2-Pyrimidinyl)-1-piperazinyl}ethoxy]-5,6,7,8-tetrahydroquinoxaline(compound 521)

Substantially the same procedure as in Example 32 was repeated, exceptthat 296 mg (1.8 mmol) of 1-(2-pyrimidiyl)piperazine was used instead of1-(2-pyridyl)piperazine, to thereby obtain 407 mg of2-[2-{4-(2-pyrimidinyl)-1-piperazinyl}ethoxy]-5,6,7,8-tetrahydroquinoxaline(compound 521) (yield: 80%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[2-{4-(2-pyrimidinyl)-1-piperazinyl}ethoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 342-[3-{4-(2-Pyridyl)-1-piperazinyl}propoxy]-5,6,7,8-tetrahydroquinoxaline(compound 537)

227 mg (1 mmol) of 2-(3-chloropropoxy)-5,6,7,8-tetrahydroquinoxaline wasdissolved in 10 ml of acetonitrile. To the resultant solution were added208 mg (1.5 mmol) of potassium carbonate, 196 mg (1.2 mmol) of1-(2-pyridyl)piperazine and 149 mg (1 mmol) of sodium iodide, and theresultant mixture was heated under reflux for 15 hours. Then, themixture was subjected to filtration to filter off insoluble substances,which were then washed with acetonitrile, to thereby obtain a filtrate.The solvent of the filtrate was distilled off in vacuo to thereby obtaina residue. The obtained residue was purified by silica gel columnchromatography. That is, the residue was charged in a column of 20 g ofsilica gel (Art7734, manufactured and sold by E. Merck, Darmstadt) andeluted with chloroform-methanol (100:1), to thereby obtain 279 mg of2-[3-{4-(2-pyridyl)-1-piperazinyl}propoxy]-5,6,7,8-tetrahydroquinoxaline(yield: 79%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[3-{4-(2-pyridyl)-1-piperazinyl}propoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 352-[3-{4-(2-pyrimidinyl)-1-piperazinyl}propoxyl]-5,6,7,8-tetrahydroquinoxaline(compound 538).

Substantially the same procedure as in Example 34 was repeated, exceptthat 197 mg (1.2 mmol) of 1-(2-pyrimidinyl)piperazine was used insteadof 1-(2-pyridyl)piperazine, to thereby obtain 198 mg of2-[3-{4-(2-pyrimidinyl)-1-piperazinyl}propoxy]-5,6,7,8-tetrahydroquinoxaline(compound 538) (yield: 56%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[3-{4-(2-pyrimidinyl)-1-piperazinyl}propoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 362-[5-{4-(2-Pyridyl)-1-piperazinyl}pentoxy]-5,6,7,8-tetrahydroquinoxaline(compound 511)

255 mg (1 mmol) of 2-(5-chloropentoxy)-5,6,7,8-tetrahydroquinoxaline wasdissolved in 10 ml of acetonitrile. To the resultant solution were added208 mg (1.5 mmol) of potassium carbonate, 196 mg (1.2 mmol) of1-(2-pyridyl)piperazine and 149 mg (1 mmol) of sodium iodide, and theresultant mixture was heated under reflux for 25 hours. Then, themixture was subjected to filtration to filter off insoluble substances,which were then washed with acetonitrile, to thereby obtain a filtrate.The solvent of the filtrate was distilled off in vacuo to thereby obtaina residue. The obtained residue was purified by silica gel columnchromatography. That is, the residue was charged in a column of 20 g ofsilica gel (Art7734, manufactured and sold by E. Merck, Darmstadt) andeluted with chloroform-methanol (100:1), to thereby obtain 160 mg of2-[5-{4-(2-pyridyl)-1-piperazinyl}pentoxy]-5,6,7,8-tetrahydroquinoxaline(compound 511) (yield: 42%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[5-{4-(2-pyridyl)-1-piperazinyl}pentoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

EXAMPLE 372-[5-{4-(2-pyrimidinyl)-1-piperazinyl}pentoxy]-5,6,7,8-tetrahydroquinoxaline(compound 512)

Substantially the same procedure as in Example 36 was repeated, exceptthat 197 mg (1.2 mmol) of 1-(2-pyrimidiyl)piperazine was used instead of1-(2-pyridyl)piperazine, to thereby obtain 212 mg of2-[5-{4-(2-pyrimidinyl)-1-piperazinyl}pentoxy]-5,6,7,8-tetrahydroquinoxaline(compound 512) (yield: 56%).

In substantially the same manner as in Example 1, the hydrochloride ofthe obtained2-[5-{4-(2-pyrimidinyl-1-piperazinyl}pentoxy]-5,6,7,8-tetrahydroquinoxalinewas obtained.

                  TABLE 9                                                         ______________________________________                                        Reference                                                                              .sup.1 H-NMR(CDCl.sub.3, TMS)                                                                         MASS                                         Example No.                                                                            δ: (J:Hz)         (FAB)                                        ______________________________________                                        1        1.7˜1.9(4H, m), 2.6˜2.8(4H, m),                                                           151                                                   8.04(1H, s)             (MH.sup.+)                                   2        1.26(3H, t, J=7.1), 1.8˜2.0(4H, m),                                                             265                                                   2.0˜2.2(2H, m), 2.49(2H, t, J=7.4),                                                             (MH.sup.+)                                            2.7˜3.0(4H, m), 4.14(2H, q, J=7.1),                                                             151                                                   4.31(2H, t, J=6.3), 7.95(1H, s)                                      3        1.26(3H, t, J=7.1), 1.7˜2.0(4H, m),                                                             279                                                   2.0˜2.2(2H, m), 2.39(3H, s),                                                                    (MH.sup.+)                                            2.49(2H, t, J=7.4), 2.6˜2.9(4H, m),                                                             151                                                   4.15(2H, q, J=7.1), 4.32(2H, t, J=6.3)                               4        0.97(3H, t, J=7.3), 1.26(3H, t, J=7.1),                                                               307                                                   1.55˜1.75(2H, m), 1.7˜2.0(4H, m),                                                         (MH.sup.+)                                            2.0˜2.2(2H, m), 2.46(2H, t, J=7.4),                                                             151                                                   2.6˜2.9(6H, m), 4.15(2H, q, J=7.1),                                     4.31(2H, t, J=6.3)                                                   5        1.24(6H, d, J=6.9), 1.26(3H, t, J=7.1),                                                               307                                                   1.7˜2.0(4H, m), 2.0˜2.2(2H, m),                                                           (MH.sup.+)                                            2.49(2H, t, J=7.4), 2.6˜2.9(4H, m),                                                             151                                                   3.2˜3.4(1H, m), 4.15(2H, q, J=7.1),                                     4.31(2H, t, J=6.3)                                                   6        0.89(3H, t, J=7.0), 1.26(3H, t, J=7.1),                                                               335                                                   1.3˜1.4(4H, m), 1.5˜1.7(2H, m),                                                           (MH.sup.+)                                            1.8˜2.0(4H, m), 2.0˜2.2(2H, m),                                                           151                                                   2.46(2H, t, J=7.4), 2.6˜2.9(6H, m),                                     4.15(2H, q, J=7.1), 4.31(2H, t, J=6.3)                               7        1.6˜2.0(8H, m), 2.7˜2.9(4H, m),                                                           223                                                   3.6˜3.8(2H, m), 4.32(2H, t, J=6.3),                                                             (MH.sup.+)                                            7.96(1H, s)             151                                          8        1.6˜1.9(8H, m), 2.40(3H, s),                                                                    237                                                   2.7˜2.9(4H, m), 3.6˜3.8(2H, m),                                                           (MH.sup.+)                                            4.33(2H, t, J=6.3)      151                                          9        0.97(3H, t, J=7.3), 1.6˜2.0(10H, m),                                                            265                                                   2.6˜2.9(6H, m), 3.65˜3.85(2H, m),                                                         (MH.sup.+)                                            4.32(2H, t, J=6.3)      151                                          10       1.23(6H, d, J=6.9), 1.6˜2.0(8H, m),                                                             265                                                   2.6˜2.9(4H, m), 3.2˜3.4(1H, m),                                                           (MH.sup.+)                                            3.6˜3.8(2H, m), 4.32(2H, t, J=6.3)                                                              151                                          11       0.89(3H, t, J=7.0), 1.2˜1.4(4H, m),                                                             293                                                   1.5˜1.9(10H, m), 2.4˜2.9(6H, m),                                                          (MH.sup.+)                                            3.65˜3.85(2H, m), 4.32(2H, t, J=6.3)                                                            151                                          12       1.8˜2.0(8H, m), 2.7˜2.9(4H, m),                                                           301                                                   3.02(3H, s), 4.2˜4.4(4H, m), 7.95(1H, s)                                                        (MH.sup.+)                                                                    151                                          13       1.8˜2.0(8H, m), 2.40(3H, s),                                                                    315                                                   2.7˜2.9(4H, m), 3.02(3H, s),                                                                    (MH.sup.+)                                            4.3˜4.4(4H, m)                                                 14       0.97(3H, t, J=7.3), 1.6˜1.7(2H, m),                                                             343                                                   1.8˜2.0(8H, m), 2.6˜2.8(6H, m),                                                           (MH.sup.+)                                            3.02(3H, s), 4.3˜4.4(4H, m)                                    15       1.24(6H, d, J=6.9), 1.8˜2.0(8H, m),                                                             343                                                   2.7˜2.8(4H, m), 3.02(3H, s),                                                                    (MH.sup.+)                                            3.15˜3.35(1H, m), 4.3˜4.4(4H, m)                         16       0.89(3H, t, J=6.9), 1.3˜1.4(4H, m),                                                             371                                                   1.6˜1.7(2H, m), 1.8˜2.0(8H, m),                                                           (MH.sup.+)                                            2.6˜2.9(6H, m), 3.02(3H, s),                                            4.3˜4.4(4H, m)                                                 17       1.8˜2.0(8H, m), 2.7˜2.9(4H, m),                                                           243,                                                  3.62(2H, t, J=6.3), 4.31(2H, t, J=5.9),                                                               241                                                   7.95(1H, s)             (MH.sup.+)                                   18       1.24(6H, d, J=6.9), 1.8˜2.0(8H, m),                                                             285,                                                  2.7˜2.9(4H, m), 3.2˜3.35(1H, m),                                                          283                                                   3.63(2H, t, J=6.3), 4.31(2H, t, J=5.9)                                                                (MH.sup.+)                                   19       1.34(3H, t, J=7.3), 1.8˜2.0(4H, m),                                                             237                                                   2.8˜3.0(4H, m), 4.30(2H, q, J=7.3),                                                             (MH.sup.+)                                            4.92(2H, s), 8.16(1H, s)                                             20       1.8˜2.0(4H, m), 2.7˜2.9(4H, m),                                                           195                                                   3.22(1H, t, J=5.8), 3.9˜4.1(2H, m),                                                             (MH.sup.+)                                            4.4˜4.5(2H, m), 8.04(1H, s)                                    21       1.8˜2.0(4H, m), 2.15˜2.3(2H, m),                                                          229,                                                  2.75˜2.95(4H, m), 3.72(2H, t, J=6.3),                                                           227                                                   4.43(2H, t, J=5.9), 7.97(1H, s)                                                                       (MH.sup.+)                                   22       1.55˜1.7(2H, m), 1.75˜1.95(8H, m),                                                        257,                                                  2.75˜2.95(4H, m), 3.56(2H, t, J=6.6),                                                           255                                                   4.28(2H, t, J=6.3), 7.95(1H, s)                                                                       (MH.sup.+)                                   ______________________________________                                    

                  TABLE 10                                                        ______________________________________                                        Compound .sup.1 H-NMR(CDCl.sub.3, TMS)                                                                         MASS                                         No.      δ: (J:Hz)         (FAB)                                        ______________________________________                                        300      1.6˜2.0(8H, m), 2.45(2H, t, J=7.4),                                                             368                                                   2.5˜2.7(4H, m), 2.7˜2.9(4H, m),                                                           (MH.sup.+)                                            3.5˜3.7(4H, m), 4.30(2H, t, J=6.3),                                                             216                                                   6.5˜6.7(2H, m), 7.4˜7.6(1H, m),                                   7.95(1H, s), 8.1˜8.3(1H, m)                                    301      1.6˜2.0(8H, m), 2.4˜2.7(6H, m),                                                           369                                                   2.7˜3.0(4H, m), 3.7˜3.9(4H, m),                                                           (MH.sup.+)                                            4.30(2H, t, J=6.3), 6.47(1H, t, J=4.6),                                                               217                                                   7.95(1H, s), 8.30(2H, d, J=4.6)                                      409      1.65˜1.8(4H, m), 1.8˜1.9(4H, m),                                                          382                                                   2.41(3H, s), 2.47(2H, t, J=7.4),                                                                      (MH.sup.+)                                            2.57(4H, t, J=5.0), 2.7˜2.9(4H, m),                                                             216                                                   3.56(4H, t, J=5.0), 4.31(2H, t, J=6.3),                                       6.6˜6.7(2H, m), 7.4˜7.55(1H, m),                                  8.19(1H, dd, J=1.5, 4.6)                                             410      1.65˜1.9(8H, m), 2.40(3H, s),                                                                   383                                                   2.46(2H, t, J=7.4), 2.51(4H, t, J=5.0),                                                               (MH.sup.+)                                            2.7˜2.9(4H, m), 3.84(4H, t, J=5.0),                                                             219                                                   4.30(2H, t, J=6.3), 6.48(1H, t, J=4.6),                                       8.31(2H, d, J=4.6)                                                   423      0.97(3H, t, J=7.3), 1.6˜1.75(6H, m),                                                            410                                                   1.75˜1.9(4H, m), 2.47(2H, t, J=7.4),                                                            (MH.sup.+)                                            2.57(4H, t, J=5.1), 2.72(2H, t, J=7.8),                                                               216                                                   2.7˜2.9(4H, m), 3.55(4H, t, J=5.1),                                     4.30(2H, t, J=6.1), 6.6˜6.7(2H, m),                                     7.45˜7.5(1H, m), 8.19(1H, dd, J=1.8, 4.6)                      414      0.97(3H, t, J=7.4), 1.6˜1.8(6H, m),                                                             411                                                   1.8˜1.9(4H, m), 2.46(2H, t, J=7.4),                                                             (MH.sup.+)                                            2.51(4H, t, J=5.0), 2.72(2H, t, J=7.8),                                                               219                                                   2.7˜2.9(4H, m), 3.84(4H, t, J=5.0),                                     4.30(2H, t, J=6.1), 6.48(1H, t, J=4.6),                                       8.30(2H, d, J=4.6)                                                   431      1.25(6H, d, J=6.9), 1.6˜1.9(8H, m),                                                             410                                                   2.47(2H, t, J=7.3), 2.57(4H, t, J=5.0),                                                               (MH.sup.+)                                            2.7˜2.9(4H, m), 3.2˜3.4(1H, m),                                                           218                                                   3.55(4H, t, J=5.0), 4.30(2H, t, J=6.1),                                       6.5˜6.7(2H, m), 7.4˜7.5(1H, m),                                   8.19(1H, dd, J=2.0, 5.0)                                             432      1.24(6H, d, J=6.9), 1.6˜1.9(8H, m),                                                             411                                                   2.46(2H, t, J=7.6), 2.51(4H, t, J=5.0),                                                               (MH.sup.+)                                            2.7˜2.9(4H, m), 3.2˜3.4(1H, m),                                                           219                                                   3.84(4H, t, J=5.0), 4.30(2H, t, J=6.1),                                       6.48(1H, t, J=4.9), 8.30(2H, d, J=4.9)                               425      0.90(3H, t, J=6.9), 1.3˜1.4(4H, m),                                                             438                                                   1.6˜1.9(10H, m), 2.46(2H, t, J=7.4),                                                            (MH.sup.+)                                            2.57(4H, t, J=5.1), 2.7˜2.9(6H, m),                                                             218                                                   3.55(4H, t, J=5.1), 4.30(2H, t, J=6.1),                                       6.6˜6.7(2H, m), 7.4˜7.5(1H, m),                                   8.19(1H, dd, J=1.5, 4.5)                                             428      0.89(3H, t, J=7.1), 1.3˜1.4(4H, m),                                                             439                                                   1.6˜1.9(10H, m), 2.45(2H, t, J=7.4),                                                            (MH.sup.+)                                            2.51(4H, t, J=5.1), 2.7˜2.9(6H, m),                                                             219                                                   3.83(4H, t, J=5.0), 4.30(2H, t, J=6.1),                                       6.48(1H, t, J=4.6), 8.30(2H, d, J=4.6)                               517      1.75˜1.9(4H, m), 2.6˜2.85(10H, m),                                                        340                                                   3.53(4H, t, J=5.0), 4.13(2H, t, J=6.8),                                                               (MH.sup.+)                                            6.6˜6.7(2H, m), 7.4˜7.5(1H, m),                                   8.03(1H, s), 8.15˜8.25(1H, m)                                  521      1.7˜1.9(4H, m), 2.60(4H, t, J=5.0),                                                             341                                                   2.65˜2.85(6H, m), 3.81(4H, t, J=5.0),                                                           (MH.sup.+)                                            4.13(2H, t, J=6.8), 6.49(1H, t, J=4.6),                                       8.03(1H, s), 8.31(2H, d, J=4.6)                                      537      1.75˜2.0(6H, m), 2.47(2H, t, J=6.8),                                                            354                                                   2.56(4H, t, J=5.1)2.6˜2.8(4H, m),                                                               (MH.sup.+)                                            3.53(4H, t, J=5.1), 4.05(2H, t, J=7.6),                                       6.6˜6.7(2H, m), 7.4˜7.5(1H, m),                                   8.01(1H, s), 8.15˜8.2(1H, m)                                   538      1.75˜2.0(6H, m), 2.47(2H, t, J=6.9),                                                            355                                                   2.50(4H, t, J=5.0), 2.6˜2.8(4H, m),                                                             (MH.sup.+)                                            3.81(4H, t, J=5.0), 4.06(2H, t, J=7.6),                                       6.49(1H, t, J=4.6), 8.02(1H, s),                                              8.31(2H, d, J=4.6)                                                   511      1.5˜1.7(4H, m), 1.75˜2.0(6H, m),                                                          382                                                   2.42(2H, t, J=7.4), 2.56(4H, t, J=5.0),                                                               (MH.sup.+)                                            2.7˜2.9(4H, m), 3.55(4H, t, J=5.0),                                     4.27(2H, t, J=6.6), 6.6˜6.7(2H, m),                                     7.45˜7.5(1H, m), 7.96(1H, s),                                           8.19(1H, d, J=4.6)                                                   512      1.55˜1.7(4H, m), 1.75˜1.95(6H, m),                                                        383                                                   2.40(2H, t, J=7.6), 2.50(4H, t, J=5.1),                                                               (MH.sup.+)                                            2.7˜2.9(4H, m), 3.83(4H, t, J=5.1),                                     4.27(2H, t, J=6.6), 6.47(1H, t, J=4.6),                                       7.95(1H, s), 8.30(2H, d, J=4.6)                                      501      1.65˜1.8(4H, m), 1.8˜1.9(4H, m),                                                          382                                                   2.39(3H, s), 2.45(2H, t, J=7.4),                                                                      (MH.sup.+)                                            2.56(4H, t, J=5.0), 2.7˜2.9(4H, m),                                     3.54(4H, t, J=5.0), 4.30(2H, t, J=6.3),                                       6.43(1H, d, J=8.3), 6.48(1H, d, J=7.3),                                       7.3˜7.4(1H, m), 7.95(1H, s)                                    502      1.65˜1.8(4H, m), 1.8˜1.9(4H, m),                                                          402                                                   2.48(2H, t, J=7.4), 2.63(4H, t, J=4.8),                                                               (MH.sup.+)                                            2.7˜2.9(4H, m), 3.40(4H, t, J=4.8),                                     4.30(2H, t, J=6.3), 6.82(1H, dd, J=5.0,                                       7.6), 7.57(1H, dd, J=1.7, 7.6), 7.95(1H, s),                                  8.18(1H, dd, J=1.7, 5.0)                                             557      1.6˜1.9(8H, m), 2.47(2H, t, J=7.4),                                                             398                                                   2.63(4H, br.s), 2.7˜2.9.4H, m),                                                                 (MH.sup.+)                                            3.45(4H, br.s), 3.85(3H, s),                                                  4.30(2H, t, J=6.3), 6.82(1H, dd, J=5.0,                                       7.9), 7.03(1H, d, J=7.9), 7.87(1H, d,                                         J=5.0), 7.95(1H, s)                                                  514      1.65˜1.8(4H, m), 1.8˜1.9(4H, m),                                                          393                                                   2.47(2H, t, J=7.3), 2.60(4H, t, J=5.0),                                                               (MH.sup.+)                                            2.7˜2.9(4H, m), 3.75(4H, t, J=5.0),                                     4.30(2H, t, J=6.3,), 6.73(1H, dd, J=4.6,                                      7.6), 7.76(1H, dd, J=2.0, 7.6), 7.96(1H, s),                                  8.33(1H, dd, J=2.0, 4.6)                                             598      1.6˜2.0(8H, m), 2.21(3H, s),                                                                    396                                                   2.41(3H, s), 2.47(2H, t, J=7.3),                                                                      (MH.sup.+)                                            2.5˜2.7(3H, m), 2.7˜2.9(4H, m),                                   3.1˜3.25(3H, m), 3.55˜3.65(1H, m),                                4.2˜4.4(3H, m), 6.67(1H, d, J=7.6),                                     7.25(1H, d, J=7.6), 7.96(1H, s)                                      500      1.6˜1.8(4H, m), 1.8˜1.9(4H, m),                                                           402                                                   2.44(2H, t, J=7.4), 2.53(4H, t, J=5.3),                                                               (MH.sup.+)                                            2.7˜2.9(4H, m), 3.55(4H, t, J=5.3),                                     4.30(2H, t, J=6.3), 6.48(1H, d, J=8.2),                                       6.59(1H, d, J=7.6), 7.35˜7.45(1H, m),                                   7.95(1H, s)                                                          524      1.37(3H, t, J=6.9), 1.65˜1.8(4H, m),                                                            412                                                   1.8˜1.9(4H, m), 2.45(2H, t, J=7.4),                                                             (MH.sup.+)                                            2.54(4H, t, J=5.1), 2.7˜2.9(4H, m),                                     3.52(4H, t, J=5.1), 4.29(2H, q, J=6.9),                                       4.30(2H, t, J=6.4), 6.05(1H, d, J=7.9),                                       6.14(1H, d, J=7.9), 7.39(1H, t, J=7.9),                                       7.96(1H, s)                                                          526      1.65˜1.85(4H, m), 1.85˜1.9(4H, m),                                                        411                                                   2.47(2H, t, J=7.3), 2.62(4H, t, J=5.0),                                                               (MH.sup.+)                                            2.7˜2.9(4H, m), 3.26(4H, t, J=5.0),                                     4.30(2H, t, J=6.3), 5.91(1H, br.s),                                           7.08(1H, dd, J=4.6, 7.6), 7.95(1H, s),                                        8.29(1H, dd, J=2.0, 7.6), 8.40(1H, dd,                                        J=2.0, 4.6), 8.47(1H, br.s)                                          539      1.6˜1.85(4H, m), 1.85˜1.9(4H, m),                                                         398                                                   2.45(2H, t, J=7.4), 2.56(4H, t, J=5.0),                                                               (MH.sup.+)                                            2.7˜2.9(4H, m), 3.53(4H, t, J=5.0),                                     3.87(3H, s), 4.30(2H, t, J=6.4),                                              6.07(1H, d, J=7.9), 6.15(1H, d, J=7.9),                                       7.40(1H, t, J=7.9), 7.96(1H, s)                                      561      1.6˜1.9(8H, m), 2.39(3H, s),                                                                    421                                                   2.40(3H, s), 2.46(2H, t, J=7.3),                                                                      (MH.sup.+)                                            2.59(4H, t, J=5.0), 2.7˜2.9(4H, m),                                     3.68(4H, t, J=5.0), 4.30(2H, t, J=6.3),                                       6.52(1H, s), 7.96(1H, s)                                             569      1.65˜1.85(4H, m), 1.85˜1.9(4H, m),                                                        396                                                   2.21(3H, s), 2.36(3H, s),                                                                             (MH.sup.+)                                            2.45(2H, t, J=7.4), 2.55(4H, t, J=5.1),                                       2.7˜2.9(4H, m), 3.52(4H, t, J=5.1),                                     4.30(2H, t, J=6.3), 6.26(1H, s),                                              6.35(1H, s), 7.95(1H, s)                                             621      1.65˜1.85(4H, m), 1.85˜1.9(4H, m),                                                        436                                                   2.47(2H, t, J=7.4), 2.59(4H, t, J=4.8),                                                               (MH.sup.+)                                            2.7˜2.9(4H, m), 3.34(4H, t, J=4.8),                                     4.30(2H, t, J=6.3), 6.95(1H, dd, J=4.6,                                       7.9), 7.84(1H, dd, J=1.8, 7.9), 7.95(1H, s),                                  8.40˜8.42(1H, m)                                               629      1.00(3H, t, J=7.4), 1.65˜1.95(10H, m),                                                          426                                                   2.45(2H, t, J=7.4), 2.55(4H, t, J=5.1),                                                               (MH.sup.+)                                            2.7˜2.9(4H, m), 3.51(4H, t, J=5.1),                                     4.18(2H, t, J=6.8), 4.30(2H, t, J=6.3),                                       6.06(1H, d, J=7.9), 6.13(1H, d, J=7.9),                                       7.38(1H, t, J=7.9), 7.95(1H, s)                                      630      1.33(6H, d, J=6.3), 1.65˜1.95(8H, m),                                                           426                                                   2.45(2H, t, J=7.4), 2.55(4H, t, J=5.1),                                                               (MH.sup.+)                                            2.7˜2.9(4H, m), 3.51(4H, t, J=5.1),                                     4.30(2H, t, J=6.4), 5.15˜5.25(1H, m),                                   6.02(1H, d, J=7.9), 6.12(1H, d, J=7.9),                                       7.37(1H, t, J=7.9), 7.95(1H, s)                                      639      1.65˜1.95(8H, m), 2.46(2H, t, J=7.4),                                                           436                                                   2.56(4H, t, J=5.1), 2.7˜2.9(4H, m),                                                             (MH.sup.+)                                            3.61(4H, t, J=5.1), 4.30(2H, t, J=6.3),                                       6.77(1H, d, J=4.9), 6.78(1H, s),                                              7.96(1H, s), 8.29(1H, d, J=4.9)                                      640      1.7˜1.95(8H, m), 2.45(2H, t, J=7.4),                                                            436                                                   2.55(4H, t, J=5.1), 2.7˜2.9(4H, m),                                                             (MH.sup.+)                                            3.61(4H, t, J=5.1), 4.30(2H, t, J=6.3),                                       6.76(1H, d, J=7.9), 6.93(1H, d, J=7.9),                                       7.56(1H, t, J=7.9), 7.96(1H, s)                                      481      1.6˜1.9(8H, m), 2.28(6H, s),                                                                    397                                                   2.4˜2.6(6H, m), 2.8˜2.9(4H, m),                                                           (MH.sup.+)                                            3.84(4H, t, J=5.0), 4.30(2H, t, J=6.3),                                       6.25(1H, s), 7.96(1H, s)                                             504      1.65˜1.8(4H, m), 1.8˜1.9(4H, m),                                                          383                                                   2.33(3H, s), 2.44(2H, t, J=7.4),                                                                      (MH.sup.+)                                            2.50(4H, t, J=5.0), 2.7˜2.9(4H, m),                                     3.83(4H, t, J=5.0), 4.30(2H, t, J=6.3),                                       6.36(1H, d, J=5.0), 7.95(1H, s),                                              8.16(1H, d, J=5.0)                                                   549      1.65˜1.85(4H, m), 1.85˜1.9(4H, m),                                                        429                                                   2.44(2H, t, J=7.1), 2.48(4H, t, J=5.0),                                                               (MH.sup.+)                                            2.7˜2.9(4H, m), 3.81(4H, t, J=5.0),                                     3.85(6H, s), 4.30(2H, t, J=6.3),                                              5.36(1H, s), 7.95(1H, s)                                             562      1.65˜1.85(4H, m), 1.85˜1.9(4H, m),                                                        413                                                   2.25(3H, s), 2.44(2H, t, J=7.9),                                                                      (MH.sup.+)                                            2.49(4H, t, J=5.3), 2.7˜2.9(4H, m),                                     3.82(4H, t, J=5.3), 3.86(3H, s),                                              4.30(2H, t, J=6.3), 5.84(1H, s),                                              7.95(1H, s)                                                          ______________________________________                                    

We claim:
 1. A compound represented by formula (1) or a non-toxic saltthereof ##STR13## wherein R¹ represents hydrogen atom or a lower alkylgroup; R² represents a pyridyl group which is unsubstituted orsubstituted with 1 to 3 substituents each independently selected fromthe group consisting of a halogen atom, a lower alkyl group, atri-fluoromethyl group, a lower alkoxy group, a carbamoyl group and acyano group, or a pyrimidinyl group which is unsubstituted orsubstituted with 1 to 2 substituents each independently selected fromthe group consisting of a lower alkyl group and a lower alkoxy group;and n is an integer of from 2 to
 5. 2. A method for producing a compoundrepresented by formula (1) or a non-toxic salt thereof, ##STR14##wherein R¹ represents a hydrogen atom or a lower alkyl group; R²represents a pyridyl group which is unsubstituted or substituted with 1to 3 substituents each independently selected from the group consistingof a halogen atom, a lower alkyl group, a tri-fluromethyl group, a loweralkoxy group, a carbamoyl group and a cyano group, or a pyrimidinylgroup which is unsubstituted or substituted with 1 to 2 substituentseach independently selected from the group consisting of a lower alkylgroup and a lower alkoxy group; and n is an integer of from 2 to 5,whichcomprises reacting, in an inert solvent, a compound represented byformula (2): ##STR15## wherein R¹ and n are as defined for formula (1)above; and X represents a reactive leaving group, with a compoundrepresented by formula (3): ##STR16## wherein R² is as defined forformula (1) above.
 3. A pharmaceutical composition for treating aserotonergic neuron-related disease, which comprises, as an activeingredient, a compound represented by formula (1) or a non-toxic saltthereof, ##STR17## wherein R¹ represents a hydrogen atom or a loweralkyl group; R² represents a pyridyl group which is unsubstituted orsubstituted with 1 to 3 substituents each independently selected fromthe group consisting of a halogen atom, a lower alkyl group, atri-fluoromethyl group, a lower alkoxy group, a carbamoyl group and acyano group, or a pyrimidinyl group which is unsubstituted orsubstituted with 1 to 2 substituents each independently selected fromthe group consisting of a lower alkyl group and a lower alkoxy group;and n is an integer of from 2 to 5.